 I have written extensively on hydroxychloroquine (HQ) in my blog. Now that the interest of society has shifted towards the COVID-19 vaccines, it’s time to do a recap of the issues I addressed related to HQ and provide a final update. 4/25/2020 President Trump advocated HQ and one his advisers criticized Dr. Fauci for questioning its effectiveness. The French doctor Didier Raoult claimed a 99.3% success rate in treating COVID-19 patients with HQ, and accounts of patients treated with HQ experiencing dramatic recoveries (Lazarus-like coming back from the dead effects) were appearing in the news. In my post, I warmed against accepting these isolated “dramatic effects” reports as a measure of a drug effectiveness, stated that the only measure of a drug’s effectiveness is clinical trials, and explained why. 6/19/2020
I addressed the claim made by some doctors that HQ is 100% effective against COVID-19, and I explained not only why it is highly unlikely, but also that this is a regular claim made by charlatans. I also explain that the best clinical trials conducted so far had not found evidence that HQ worked. 7/3/2020 I debunked the misinformation that Dr. Fauci is aligned with powerful pharmaceutical interests to hamper the adoption of HQ as a life saving drug, and that Dr. Fauci already knew HQ worked more than 15 years ago. I also addressed the issue of the articles claiming that HQ did not work and was harmful. I argued that the fact that these articles were published in medical journals and then retracted is not a conspiracy but rather indicate that science worked the way it should. I also debunked the notion that countries that had embraced the use of HQ were doing better. 7/25/2020 I decried the politization of HQ and the notion that it is “the president’s drug”, and I outlined the evidence at the time against HQ which indicated it’s not effective against COVID-19. 8/8/2020 I debunked in more detail the conspiracy that Fauci knew about HQ being effective, and I proceeded to explain a bold hypothesis that explains why HQ alone does not work against COVID-19. 8/20/2020 I debunked the notions that high doses of HQ were used in some clinical trials to make HQ fail, or that pharmaceutical companies want to eliminate HQ because it’s a cheap alternative to their expensive drugs. Since some HQ proponents were then arguing that HQ only works with zinc (the zinc hypothesis), I pointed out that this contradicted their cheering of studies where HQ allegedly worked alone (which it shouldn’t have if it only works with zinc). 9/12/2020 I examined the difference between doctors and scientists and debunked the notions that “doctors know best” and that “we don’t need randomized trials”. I also described the important role of the scientific establishment in science. 9/18/2020 I explained why observational trials cannot provide the final evidence that HQ works, and I pointed out that even the authors of the studies that the pro-HQ folk cite in favor of HQ state that randomized trials are needed. 10/16/2020 Despite the evidence which indicated that HQ did not work alone or with antibiotics, some HQ proponents still supported the hypothesis that HQ worked as long as you combined it with zinc. In this post I explained the evidence against HQ alone or with zinc. I also explained why it is important to remain objective and not fall in love with your hypotheses. 10/24/2020 In this final post, I readdressed the conspiracy theory that claimed that the clinical trials of HQ were designed to make it fail. I also examined the accusation that Dr. Fauci’s unwillingness to accept that HQ works was killing people. Update As I have mentioned before, to reach a conclusion regarding the activity of HQ on COVID-19 you need to focus on the studies that allocate patients to treatments at random (randomized studies). There are people that keep pushing the claim that HQ does work based on the total number of studies performed on the drug, which includes the observational (non-randomized) studies which are of lower quality because they are prone to bias. I searched a database for randomized studies of HQ and COVID-19, and only two of the studies I found were positive for the drug (1, 2), whereas 25 other studies were negative (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25). However, whether HQ works or not cannot be established merely by counting the number of pro and con studies. Even among randomized studies, some studies are of lower quality than others. One or two high-quality studies can trump many low-quality studies. In order to evaluate the merits of studies in addressing whether HQ works for COVID-19, scientists perform analyses (studies of studies) where they assess the quality and relevance of the studies. Throughout the COVID-19 pandemic several of these analyses have been performed. I searched the database for these analyses and I found 20 of them, all negative for HQ (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20). The conclusion is inescapable, hydroxychloroquine DOES NOT work for COVID-19. Period, end of the discussion. The breathtaking number of studies conducted on this drug is a testament to its politicization. The sheer amount of manpower and resources devoted to testing HQ was unjustified when a handful of studies would have sufficed. The attacks and lies hurdled against scientists including Dr. Fauci because they refused to accept that HQ works based on the available data was unethical. From Mr. Trump who unwisely promoted the drug to individuals such as the epidemiologist Harvey Risch and Dr. Vladimir Zelenko or groups such as the Front-Line Doctors who all claimed the drug worked even when the best evidence indicated otherwise, this saga has been a lesson on what people should not do with science and in science. Unfortunately, these people have not learned their lesson and still claim to have been right all along. Such is the complexity of the human mind. Image by WHO-openaccess was cropped from a PNG file by Cantons-de-l'Est and is used here under a Creative Commons Attribution-ShareAlike 3.0 IGO license, and was modified to include the name and formula of hydroxychloroquine.
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 The Conspiracy Theory that Went Bust Some of the proponents of the drug hydroxychloroquine (HCQ) have put forward a conspiracy theory to explain the negative results for the drug in some clinical trials. They claim that the scientists running the trials have sold out to pharmaceutical companies and designed the trials in such a way as to make HCQ fail the trials. The alleged reason for doing this is to favor more expensive alternatives such as the drug remdesevir from Gilead Sciences and vaccines or antibodies made by other companies. This convoluted conspiracy theory has grown to encompass a worldwide network of scientists that have sold out in this fashion and to even involve organizations such as the Gates Foundation and the World Health Organization that are also allegedly colluding with the pharmaceutical companies. This vast network of colluding scientists from different countries using different sources of funding and engaging in behavior contrary to the principles of the organizations for which they work, is not only very unlikely but the most basic tenets of the conspiracy theory are not even coherent. I have mentioned before that the same trial that found that HCQ was not effective against COVID-19 (the Recovery trial), also found that dexamethasone was effective in advanced cases of the disease. Steroids like dexamethasone are cheap generic drugs. Why would scientists colluding with pharmaceutical companies design the trials to torpedo one cheap drug (HCQ) but not another one (dexamethasone)? But there is more. Recently the results of the Solidarity trial sponsored by the World Health Organization (WHO) were published. It was already known that the trial had not found HCQ to be effective and this fanned the conspiracy theory, but another result of the trial was that remdesivir was not effective too! Why would the WHO betray their pharma overlords by trashing their drug? The answer is that the WHO didn’t because there was no one to betray. The vast majority of scientists involved in this research are honest individuals who are genuinely interested in finding whether these drugs work against a terrible disease. These scientists designed and performed clinical trials to the best of their abilities to obtain answers. This is how science is supposed to work. No ulterior motives, no deceit, and no conspiracy: just the facts, the evidence, and the truth.  Dr. Anthony Fauci The Accusation that Fell Flat The attacks on Dr. Anthony Fauci continue due to his resistance to accept that hydroxychloroquine works. Dr. Fauci has stated: “The point that I think is important, because we all want to keep an open mind, any and all of the randomized placebo-controlled trials, which is the gold standard of determining if something is effective, none of them had shown any efficacy by hydroxychloroquine. Having said that, I will state, when I do see a randomized placebo-controlled trial that looks at any aspect of hydroxychloroquine, either early study, middle study, or late, if that randomized placebo-controlled trial shows efficacy, I would be the first one to admit it and to promote it. But I have not seen yet a randomized placebo-controlled trial that’s done that. And in fact, every randomized placebo-controlled trial that has looked at it, has shown no efficacy. So, I just have to go with the data. I don’t have any horse in the game one way or the other, I just look at the data.” This is the comment we would expect from a scientist like Dr. Fauci, Just show him a well-designed study that shows that HCQ is effective and he will change his mind. Makes sense right? But no, HCQ proponents will have none of it. They claim the evidence for HCQ is overwhelming (it isn’t), but it is being suppressed by a massive disinformation campaign (which is really an attempt by responsible organizations and individuals to counter misinformation about HCQ). And they have found another way to attack Dr. Fauci. They claim that the lack of acceptance of the effectiveness of HCQ by Fauci is killing people! The Yale epidemiologist Harvey Risch and others have stated that back in the 1980s Dr. Fauci refused to issue guidelines for physicians to consider the prophylactic use of an antibiotic (Bactrim) to prevent an opportunistic infection (pneumocystis pneumonia) in AIDS patients because he considered there was not enough data, and this led to the preventable deaths of 17,000 people. They claim that Fauci is doing this again with HCQ and that people who could be saved are dying. This new accusation has reached a fevered pitch with claims that Dr. Fauci is a mass murderer. The notorious HCQ proponent Vladimir Zelenko is circulating a petition to the White House to bring several individuals including Dr. Fauci to justice for “Crimes Against Humanity / Mass Murder”. There are several things that have to be understood by Fauci’s critics. The first is that, as I have explained before, the job of doctors is to save their patients and improve their lives, and doctors have the freedom to treat patients as they see fit. On the other hand, the job of scientists like Fauci is to try to figure out what works and what doesn’t based on the evidence. During times when a disease ravages society, the use of many drugs that may or may not work is often proposed. These drugs can be prescribed by doctors, but they should not be endorsed by scientists. There is a scientific discussion that has to take place and the evidence has to be generated and/or evaluated. Dr. Fauci cannot endorse a drug for which the evidence is deficient. In any case Dr. Fauci himself has stated that he had no authority to issue guidelines, but he offered to help with carrying out a clinical trial. The second thing is that Fauci is not the type of callous person that he is made out to be by HCQ proponents. Just consider that their accusations are remarkably similar to those levied upon Fauci by the notorious AIDS activist Larry Kramer back in the 1980s who besides calling him a murderer also said Fauci was a Nazi who should be put in front of a firing squad. Larry Kramer eventually befriended Fauci and he and other AIDS activists worked together with Fauci to make improvements to the clinical trial system which has saved many lives and given patients more control over the process. And finally, just consider Fauci’s achievements. Apart from what I mentioned above regarding the modification of the clinical trials system, Fauci has not only made many scientific contributions that have advanced our knowledge of disease as well as developing effective therapies against diseases, but he has been among the architects of major programs such as PEPFAR (President's Emergency Plan for AIDS Relief) which has saved the lives of 18 million (!) people in Africa. In recognition for his work in creating the PEPFAR program, President George W. Bush awarded him the Presidential Medal of Freedom in 2008. Fortunately, this accusation by HCQ proponents that Fauci is a murderer has fallen flat. The vast majority of people understand that Dr. Fauci is an exceptional individual both as a scientist and as a person. The vast majority of people also understand that those levying these accusations against Fauci have now pushed themselves further into a fringe and lost all credibility. The image of Dr. Fauci ny NIAID is used here under an Attribution 2.0 Generic (CC BY 2.0) license. The conspiracy sign by Nick Youngson from Picpedia.Org (used here under a Creative Commons 3 - CC BY-SA 3.0 license), the public domain image of hydroxychloroquine by Fvasconcellos, and the public domain coronavirus image by Alissa Eckert, MS; Dan Higgins, MAM, from the CDC's Public Health Image Library were modified and merged.
One of the things you learn as a scientist is to be skeptical of stories. By stories I mean narratives that scientists have put together to try to explain certain observations, to explain how some things work, or to suggest new ways of doing things that may be more effective than the old approaches. And the way you learn to be skeptical of stories is through the experience of witnessing countless numbers of them crash and burn over the years. We scientists try to discover reality, but the problem is that reality is often more complicated and nuanced than we can imagine. The English biologist Thomas Huxley once encapsulated this in his famous dictum: The great tragedy of Science—the slaying of a beautiful hypothesis by an ugly fact.  Because scientists are human, they tend to fall in love with their ideas and bring to the front in their arguments all the evidence that suggests those ideas are true while overlooking evidence that indicates the opposite. But thankfully these biases are countered by experience. As a scientist, I have lost track of how many times I thought I understood how things worked only to have my ideas disproved by the next experiment. As a scientist, I have also lost track of the number of times I became enamored of a beautiful idea proposed by a scientist only to read later that another scientist had performed an experiment that refuted it. After years of being exposed to this process, you tend to be wary of anything new that sounds too good, and this experience is a fundamental part of the development of a skeptical scientific mindset. I remarked before that one of the problems we have in science communication is that now people without training as scientists have access to information intended only for experts. The vast majority of these people do not have the experience I outlined above. As a result of this, I am witnessing many of these individuals become infatuated by unverified hypotheses to the point of aggressively defending them in social media and arguing that these hypotheses have been proven to be true by what is nothing but substandard evidence. A case in point is the hypothesis that hydroxychloroquine (HCQ) and/or its combination with zinc is effective against COVID-19. Hydroxychloroquine (HCQ)
HCQ and its parent compound chloroquine (CQ) have been used for decades against malaria. But the original interest in using HCQ against COVID-19 was generated as a result of studies that indicated CQ had antiviral activity against various viruses including SARS-Cov, a virus related to SARS-Cov-2 which produces COVID-19. More recent studies found that HCQ does indeed have antiviral activity against SARS-Cov-2. Unfortunately, this antiviral activity was evaluated in cultured green monkey kidney (Vero-E6) cells. When HCQ was tested in human airway cells or animal models, no such activity was found. Thus the initial rationale that got scientists interested in using HCQ against COVID-19 has evaporated. If we knew at the start of the pandemic what we now know about HCQ’s lack of antiviral activity against SARS-Cov-2, HCQ would never have been tested against COVID-19. This lack of antiviral activity probably explains why HCQ has not been found to be effective against COVID-19 in the best designed trials (1, 2, 3, 4, 5, 6, 7, 8, 9). Nevertheless, HCQ proponents claim that other effects of HCQ such as its anti-inflammatory actions can produce a protective effect against COVID-19. HCQ does indeed have well-documented anti-inflammatory action in diseases such as lupus or rheumatoid arthritis. However, the onset of this action is slow taking several weeks to months for patients to begin to see improvements, with the full effects taking as much as a year or more. In comparison, the time frame of HCQ treatment in COVID-19 is a couple of weeks at most. And in case you are wondering, studies indicate that patients with lupus or rheumatoid arthritis who were taking HCQ were not protected from COVID-19. There is some evidence that in patients with COVID-19 treated with HCQ there is a faster onset of anti-inflammatory action, but it is not clear why HCQ would be better than other anti-inflammatory agents or why the anti-inflammatory properties of HCQ did not make a difference in the best designed trials. Zinc and HCQ Another hypothesis for a possible HCQ action against COVID-19 involves the trace element, zinc. HCQ proponents claim that HCQ taken with zinc is a very effective therapeutic for COVID-19. Zinc has been found to have antiviral action in cell culture because it inhibits the enzyme necessary for the replication of the virus’ genetic material. Additionally, zinc deficiency compromises normal immune function and there is some evidence that zinc deficiency results in a worse COVID-19 outcome. So giving zinc to people with COVID-19 seems like a good idea to correct any zinc deficiency. In fact one of the treatments that the president received when he was infected with COVID-19 was zinc supplements (but not HCQ). So you may ask, if a COVID-19 patient is receiving zinc, why also coadminister HCQ? Some HCQ proponents argue that in physiological conditions zinc is a charged molecule that has trouble getting across cell membranes, and HCQ in a cell culture study was found to act like a zinc ionophore. This means it increases zinc uptake into cells. Therefore the claim is that you administer HCQ with zinc to “help” zinc get inside the cells where it can inhibit the virus. In this view, it is zinc that has the antiviral action while HCQ only helps it get into cells. The issue with this notion is that zinc has no problems getting across cell membranes. There are zinc transporters in the membranes of cells that can let zinc in (and out) just fine. In fact, 99.9% of the zinc in the body is inside the cells. Regardless, HCQ proponents argue that HCQ is necessary to drive the uptake of an excess amount of zinc to produce antiviral effects. In the cell culture study mentioned above (and bearing in mind that these are cell culture results with all of their caveats), a concentration of 10 micromolar HCQ outside the cells increased intracellular zinc slightly above two times the normal amount. Whether this is enough to antagonize viral replication is an open question. However, the majority of the intracellular zinc was targeted to a compartment called a lysosome (which is where HCQ accumulates). The problem is that viral replication takes place elsewhere in the cell (the cytosol). How can zinc trapped in the lysosome affect extralysosomal viral replication? And increasing the HCQ concentration outside the cell to push in more zinc is problematic. In humans, HCQ plasma concentrations greater than 15 micromolar are associated with mortality (reference: download pdf). An additional complicating factor is that the majority of the zinc both inside and outside the cells is not free. It is bound to proteins. Zinc is used as a signaling molecule by cells and if its levels are allowed to increase in an uncontrolled fashion, they can be toxic. Cells control their internal free zinc levels and try to keep them as low as possible. I am greatly skeptical about the effectiveness of HCQ against COVID-19, because I consider that the best evidence we have indicates it doesn’t work. I am also skeptical about the zinc story. There are too many questions and a lot of it remains unproven. The effect of zinc alone may be to correct a deficiency as opposed to a pharmacological effect, and HCQ may have no role in the process. But as I have stated before, I want to save lives, not be right. If HCQ alone is found to work against COVID-19 in some specific dose modality or temporal dosing regimen, then that’s great. If zinc combined with HCQ is better than HCQ alone, then that’s great too. But we need well-designed clinical trials to prove this (which excludes observational studies). In the meantime we will all be best served if we maintain a reasonable level of skepticism. My message to HCQ proponents is: Avoid falling in love with the story. Heart image by Mozilla used here under a Creative Commons Attribution 4.0 International (CC BY 4.0) license was modified from to include the words of hydroxychloroquine and zinc with the heart on a white background.  A series of randomized trials of hydroxychloroquine (HCQ) have indicated that it doesn’t work against COVID-19 as a single agent or with antibiotics (1, 2, 3, 4, 5, 6,and 7). HCQ proponents have criticized these trials putting forward many arguments. Two of the main arguments are that the doses were too high and that HCQ was not administered with zinc. In response to that, HCQ skeptics like me have argued that we should then wait for the results of randomized trials of lower doses of HCQ or HCQ with zinc. Some (but not all) HCQ proponents reply to this by stating that randomized trials are not necessary because numerous observational (non-randomized trials) have shown that HCQ works. When it is pointed out to them that these observational trials have the potential to be biased due to their non-randomized nature, these HCQ proponents reply that randomized trials have shortcomings too, and that the observational trials that have been performed are all the evidence we need. So how do we resolve this argument? It occurred to me that I would look at some of the observational trials that HCQ proponents defend, and see what the authors of these trials have to say about the matter. Here are their comments:
Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19 This is the controversial Henry Ford study. The authors state that: “Our results also require further confirmation in prospective, randomized controlled trials that rigorously evaluate the safety and efficacy of hydroxychloroquine therapy for COVID-19 in hospitalized patients.” COVID-19 outpatients – early risk-stratified treatment with zinc plus low dose hydroxychloroquine and azithromycin: a retrospective case series study (Click on Get pdf) This is the study by the controversial HCQ apologist Vladimir Zelenko. He and his coauthors state that one of the limitations of their study is that it is a: “Retrospective case series study with findings that have to be validated in prospective controlled clinical trials.” Low-dose hydroxychloroquine therapy and mortality in hospitalised patients with COVID-19: a nationwide observational study of 8075 participants This is the large nationwide study from Belgium. The authors state that: “Although observational studies, even of large scale, do not provide final conclusions on treatment efficacy, their results are important to consider in order to guide clinical trials. Well-designed prospective studies combined with large, randomised control trials should provide definitive evidence about the clinical impact of HCQ in severe hospitalised and in mild ambulatory COVID-19 patients.” Use of hydroxychloroquine in hospitalised COVID-19 patients is associated with reduced mortality: Findings from the observational multicentre Italian CORIST study This is the large study from Italy. The authors state that: “Within the limits of an observational study and awaiting results from randomized controlled trials, these data do not discourage the use of HCQ in inpatients with COVID-19.” The Effect of Early Hydroxychloroquine-based Therapy in COVID-19 Patients in Ambulatory Care Settings: A Nationwide Prospective Cohort Study This is a large study from Saudi Arabia. The authors state that: “Additional large randomised controlled trials are recommended to further support this conclusion, particularly in older populations.” Effect of combination therapy of hydroxychloroquine and azithromycin on mortality in COVID-19 patients This is a smaller study from Italy. The authors state that: “There are also several limitations to acknowledge. A first limitation relates to the study design, as we performed a single-center observational study, which does not allow to completely correct for confounders. Only a randomized double-blind clinical trial would provide more solid evidence.” Risk Factors for Mortality in Patients with COVID-19 in New York City This is a New York study involving several hospitals and ambulatory practices. The authors state that: “Due to the inherent limitations of our retrospective study design, there was no conclusive determination on the efficacy of hydroxychloroquine in patients with COVID-19. More robust studies such as randomized clinical trials are needed.” Effectiveness of hydroxychloroquine in COVID-19 disease: A done and dusted deal? Another study from Italy. The authors state that: “…we believe that hydroxychloroquine should be further tested in randomised trials. When best to start treatment is also a question that needs to be addressed in ad-hoc randomized studies.” So the authors of all the above observational studies often cited by some HCQ proponents as definite proof that HCQ works and that we don’t need randomized trials, acknowledge the need for randomized trials or accept that randomized trials would provide more robust confirmatory information. And how couldn’t they? The randomized trial is the gold standard of clinical medicine. The majority of scientists and doctors know and accept this. And in case you are wondering, the observational studies that yielded a negative result for HCQ also make the same kind of statements (for example: A, B, C, D, E, and F). The majority of the authors of the studies mentioned above are not “for” or “against” HCQ. They just wanted to find if the drug worked, and they did what they could with what they had during the difficult setting of a pandemic. I respect that, but as they acknowledge (and I have repeatedly pointed out in my blog), to firmly establish or confirm that HCQ works in a given treatment modality or dosage, we need the randomized trials. Clinical trials image from pixabay by mcmurryjulie is free for commercial use.  I have been posting on social media about the COVID-19 pandemic, and I have encountered a series of misconceptions that people have about doctors, scientists, and the scientific establishment, so let me address them in this post. Doctors and non-physician scientists have been trained in the methods and ways of science, so in that sense they are both scientists, but with one important distinction. The goal of doctors is to save and improve the lives of their patients, and that is even more so during the COVID-19 pandemic. However, the goal of scientists is to figure out what drugs and treatments actually work. Scientists need time to carry out research, but most doctors often don’t have time. The patient is sick NOW and may die, so what do we do? That is the question doctors have to answer in a hurry. When dealing with a disease that has many unknowns such as COVID-19, doctors often have to improvise. This is why doctors have (within reason) freedom to treat their patients as they see fit in consultation with them, although this freedom is regulated by the law, and may be restricted further if the doctor belongs an institution or organization that adheres to certain policies. While doctors and scientists understand that this freedom to deal with a patient’s illness is necessary, both doctors and scientists also understand that, barring some drug or treatment that is exceptionally effective, any treatments doctors come up with can only be validated by well-designed clinical trials. In fact, the majority of doctors will modify their treatments based on the results of clinical trials. Observational studies, where patients are sorted into treated and non-treated groups in a retrospective fashion, are highly prone to biases and cannot substitute for randomized trials. The authors of any such study will state as much when discussing the limitations of their study. This fact is widely accepted by the medical and scientific communities. However, when treating patients doctors deal with situations that often go beyond the mere effectiveness of a drug. For example, if a patient is strongly convinced that a worthless drug will help him or her, the doctor may choose to prescribe the drug anyway (if it is safe) just to exploit the placebo effect.
So next time you hear somebody not trained in science or even some doctors and some scientists say things such as, “Doctor’s know best.” or “We don’t need randomized trials.” or even “We don’t need any trials.”, remember that they represent a minority of all the doctors and scientists who know what works best and how. Now let’s deal next with the scientific establishment. The scientific establishment has been getting a bad rap lately. A series of individuals and groups have gone to the press and social media to claim that the scientific establishment has aligned itself with the interests of pharmaceutical companies to promote their expensive and dangerous drugs or vaccines while rejecting cheap alternatives like hydroxychloroquine (HCQ). They allege that the scientific establishment has known for more than a decade that HCQ works against viruses like the one that causes COVID-19. They allege that the scientific establishment was involved in designing the HCQ trials with high toxic doses on purpose so the negative results could be used against the drug. They allege that the scientific establishment was responsible for the publication of articles based on fraudulent data against HCQ in top journals to give the drug a bad name. And finally they allege that those who reject HCQ are complicit in the murder of tens of thousands of Americans! I have addressed several aspects of these arguments before, so I will only do a brief recap here. The evidence for HCQ having activity against a virus similar to COVID-19 was very preliminary, and turned out to be misleading (see below). Of all the drugs submitted for approval to the FDA, only 14% are approved, and the same trial that found no effect of HCQ (the Recovery Trial) found an effect of steroids, which are cheap generic drugs. Why would this be the case if the scientific establishment is a puppet of big pharma? The HCQ trials were designed with those high doses to favor HCQ, which was considered to be a weak antiviral (now we know that HCQ has no antiviral activity against COVID-19). And those articles based on fraudulent data were retracted. Error was detected, addressed, and eliminated. This is how science should work. I have not addressed the “thousands of deaths” argument before, so I will devote a few sentences to it. Someone honestly convinced about the effectiveness of a therapy and concerned about the lives of patients may use this argument sincerely. However, this argument is a double edged sword, because it is a common subterfuge employed by quacks as a form of emotional blackmail to get worthless therapies or products approved without scrutiny. Many doctors and scientists upon hearing this argument will immediately adopt an adversarial or at least unsympathetic position, because the assumption is that you don’t have the science that it takes to back your claims. So it is not a good idea to use it. When addressing the scientific establishment, you are better served using the common language of evidence, facts, and science. The scientific establishment fulfills an important role in science. The scientific establishment is the keeper of the virtue of science. It protects science against fraud and error. It protects science against dangerous, unproven, or just merely stupid ideas. It protects science against the “unreasonable men”. The scientific establishment is conservative and sets a high bar for the acceptance of evidence. While the scientific establishment has made mistakes in rejecting ideas that were true (although sometimes rightfully so), the overall effect of the scientific establishment is a positive influence upon science. But who or what is the scientific establishment? Critics of the scientific establishment tend to equate it with the leaders of scientific institutions who have the power. This is not true. While the scientific establishment has centers of power, it is made up of millions of voices, each contributing to the debate at different levels and vying to be heard. The scientific establishment is the combined effect of the scientific community. From those scientists who work in labs, to those who perform clinical trials. From those scientists who perform research to those who teach and communicate science to society. From those scientists who advise the heads of government, to those who criticize them, and those who criticize the critics. Although the scientific establishment contains a vast marketplace of ideas, it has a tried and true method to discern which ideas are true and which are not: the scientific method. And one of the things on which the vast majority of scientists agree is that they are unwilling to yield to any pressure that involves compromising this method. Image from Pixabay by Peggy_Marco is in the public domain. 8/20/2020 Hydroxychloroquine: There are Arguments and Counterarguments, but You Can't Have it Both WaysRead Now I have had several exchanges with the folks that argue that hydroxychloroquine (HCQ) is an effective treatment for COVID-19, and in this post I want to go over some of the arguments and counterarguments that have been bouncing around the internet, and try to make sense of them within a logical framework. Other posters and I have pointed out to the HCQ proponents that the best-designed studies have not found any effects of HCQ administered alone or with antibiotics (1, 2, 3, 4, 5, 6,and 7). In response to this, the HCQ proponents argue that these studies used HCQ doses that were too high and even (they claim) toxic for the study participants. Some HCQ proponents have suggested that these high doses were administered on purpose to make the HCQ groups in the studies fail, and they infer a nefarious purpose behind this, such as the study authors selling out to Big Pharma to discredit a cheap treatment for COVID-19 (HCQ) in favor of vastly more expensive treatments. Why did these studies use these high doses? There was nothing nefarious about choosing those high doses. It was done according to scientific rationales based on mathematical models that incorporate parameters such as the absorption, distribution, metabolism, and excretion of HCQ, and its activity against the virus in cell culture, coupled to the understanding that administering a short course of HCQ for a viral infection (which requires rapid drug penetration into tissues for effective prompt antiviral activity), is different from dosing HCQ for chronic conditions like rheumatoid arthritis or lupus. Specifically, not only is HCQ a weak antiviral, but HCQ has what is called a large volume of distribution. This is a pharmacokinetic parameter that describes the amount of a drug present in plasma in relation to the amount present in the rest of the body. Drugs (such as HCQ) with a high volume of distribution take longer to reach therapeutic concentrations in the blood, and require a loading dose to quickly reach the therapeutic concentration, followed by maintenance doses to sustain these therapeutic concentrations.
The dosing in these studies was carefully engineered based on knowledge of known toxicity of chloroquine overdoses and other considerations to achieve high HCQ concentrations while minimizing toxic side-effects. The high doses actually favored HCQ. If these studies had used the low doses that HCQ proponents advocate in social media, the studies would have been open to the criticism that the doses the studies used were not high enough for HCQ to be effective! I want to also dispel the notion that HCQ is being shot down because it is a cheap therapy from which Big Pharma will not profit. One of the trials that did not find an effect of HCQ, the Recovery Trial, did find an effect of steroids in reducing mortality for patients with COVID-19 receiving respiratory support, and steroids are generic cheap medicines which are now being used successfully to save the lives of COVID-19 patients. If Big Pharma could control the outcome of the HCQ arm of the study, why would it allow the steroid arm of the trial to succeed depriving them of millions of dollars they could have earned with their expensive therapies? Make no mistake: If HCQ alone or with antibiotics had been found to be effective, we would have seen it in the Recovery trial and the rest of similarly well-designed clinical trials. Further evidence against HCQ as a single agent that I’ve mentioned before, includes: 1) People who suffer from lupus and were taking HCQ when the pandemic started, were not protected from COVID-19 compared to those lupus patients that were not taking HCQ, and 2) HCQ does not protect macaque monkeys or hamsters against COVID-19. Additionally, as I have also mentioned before, HCQ has been found to have no antiviral action in cells from the human airways, which is probably due to the inability of HCQ to block a specific pathway of viral entry into these cells. Under the massive weight of the evidence some of the HCQ proponents have reluctantly admitted that HCQ alone does not work against COVID-19, but they claim that this is irrelevant because HCQ was not coadministered with zinc. The so called “zinc hypothesis” of HCQ action states that it is zinc that has the antiviral action (it prevents replication of the virus), and that the role of HCQ is to facilitate the entry of zinc into the cells. HCQ proponents claim that the clinical trials using HCQ alone are silly because HCQ is being used in a fashion that won’t be effective (i.e. without zinc). All the clinical trials I mentioned above with HCQ as a single agent or with antibiotics, but no zinc, were designed and commenced in the early phase of the pandemic when zinc was not part of the argument. The initial trials that brought HCQ to the attention of the world and the initial hypothesis of HCQ action did not involve zinc. Scientists were testing the hypothesis that was current at the time. This is perfectly reasonable and understandable. However, at least one clinical trial did analyze a subset of patients who were taking zinc supplements (scroll down to table S8) and found that this did not make a difference in the treatment outcome. But because this was not part of the treatment of the formal study protocol, this result is not conclusive. There are several ongoing clinical trials that include hydroxychloroquine and zinc, so we are waiting for those results to decide if the combination of HCQ and zinc works Finally, I need to address an issue that I have seen played out over and over in social media. HCQ proponents dismiss again and again any HCQ trial that does not combine the drug with zinc, but at the same time cheer and defend the results of trials that find a positive effect for HCQ even if it was not used with zinc, such as the one from Dr. Raoult’s lab or the one from the Henry Ford Health System. And when these trials are criticized for having biases that compromise their interpretation (which they do: big time), HCQ proponents lash out at the critics and insult them calling them stooges of the establishment who have sold out to Big Pharma interests that want to shoot down HCQ even if it kills tens of thousands of Americans. If HCQ does not have an antiviral activity of its own and just acts as a facilitator for zinc to enter the cell and stop viral replication (like the zinc hypothesis proposes), then trials that use HCQ alone SHOULD NOT work. You can, of course, argue that other effects of HCQ besides getting zinc in can produce some positive results, but they would certainly be far from stellar. The fact that trials such as the one from Dr. Raoult’s lab or the Henry Ford Health System found impressive results with HCQ alone actually raises a huge red flag, because they indicate the extent of the biases that compromised the interpretation of the results. This is why we can’t rely on observational studies like these to come to meaningful conclusions. My message to HCQ proponents is that science is about discriminating between alternative hypotheses. If you argue that the best trials found no effect because you need to administer HCQ with zinc in order for the therapy to work, you can’t argue at the same time that HCQ has great effects on its own. You can’t have it both ways. Yin Yang Image by Gregory Maxwell and the image of hydroxychloroquine by Fvasconcellos are in the public domain and were modified 8/8/2020 Cultured Cells, Dr. Fauci, and a Bold Hypothesis to Explain Why Hydroxychloroquine Alone Doesn't Work for COVID-19Read NowHow did the notion arise that hydroxychloroquine could be used against the SARS-CoV-2 virus that causes COVID-19? I want to spend some time on this because it involves an article that is often quoted to slander Dr. Fauci.  Vero E6 Cells in Culture and Hydroxychloroquine In 2005 there was a study where chloroquine (a drug related to hydroxychloroquine) was found to be effective at reducing infection with the virus, SARS-CoV (which is 79% related to the COVID-19 virus, SARS-Cov-2), in primate cells in culture. Early on in the COVID-19 pandemic, it was claimed that Dr. Fauci was lying when he said that there was no good evidence for the effectiveness of hydroxychloroquine against COVID-19 because he has known about this article for 15 years. This claim is still being made over and over in social media, and has even been retweeted by some high profile people in the hydroxychloroquine debate.
Any scientist who has worked with cells in culture (for example, me) will tell you that extrapolating from cultured cells to the full organism is fraught with peril. The metabolism of cells in culture and the way they react to chemicals or biologicals can be substantially different from the way they react as part of the full organism. In the full organism, cells are in a three dimensional matrix, interacting with other cells types and exposed to the daily cycles of fluctuations in levels of nutrients, hormones, temperature, oxygen, etc. Also, any drugs delivered to the organism, depending on the mode of delivery, may have to pass through several layers of other cells before they reach their intended target. In culture, the cells are in a two dimensional environment interacting only with cells like themselves under fixed conditions. When you deliver a drug to the cells in culture, it reaches them right away. So, more often than not, what you get using cell culture, is different from what you get in the full organism. Additionally, the cells used in the study mentioned above were Vero E6 cells. This is a cell line derived from the kidney of an African Green Monkey, and these cells even have a different number of chromosomes compared to those of the original monkey. Infecting cultured cells from the kidney (not the airways) of a monkey (that are different from human cells and even from the cells of the original monkey) with the SARS-Cov virus (which is different from the COVID-19 virus), treating them with chloroquine (which is different from hydroxychloroquine), and then extrapolating the results to the full human being to argue that Dr. Fauci “…has known for 15 years that chloroquine and it’s even milder derivative hydroxychloroquine (HCQ) will not only treat a current case of coronavirus (“therapeutic”) but prevent future cases (“prophylactic”).” is scientifically inaccurate, to say the least. Then why do scientists use these monkey cells to test compounds against viruses that infect humans? The answer is that these cells can be infected with many viruses and they are a convenient, but very preliminary, test that can be used to screen many compounds quickly, and identify those that display activity against viruses. Once a compound is identified, it is subjected to more complex tests that may involve human cells and studies with whole animals to see if it still works. As it turns out, hydroxychloroquine has been recently been tested with these Vero E6 cells, and it has been found to have antiviral activity against the SARS-CoV-2 virus. But can hydroxychloroquine stop the COVID-19 virus from infecting cells from the human airway, which is the main site of entry of the virus into the body? A study performed with reconstituted airway epithelium developed from primary human nasal or bronchial cells indicated that hydroxychloroquine had no activity against the COVID-19 virus. Why would this be the case? A group of researchers have proposssed a very clever answer to this question. There are two ways that the COVID-19 virus can get into a cell. One involves the uptake of the virus into an intracellular compartment called the “endosome”. The endosome is a compartment that is acidic which is optimal for the functioning of an enzyme called Cathepsin L (CatL) that acts on the virus and activates it. One of the effects of hydroxychloroquine is to lower the acidity of the endosome which impairs the activity of CatL and thus hinders the activation of the virus. However, the cells of the human airway epithelium have low levels of CatL. In these cells, the entrance of the virus is achieved through a second route involving activation by an enzyme called TMPRSS2 which is not dependent of endosomes or acidity and is therefore not affected by hydroxychloroquine. Thus the CatL (hydroxychloroquine sensitive) pathway is predominant in Vero E6 cells, whereas the TMPRSS2 (hydroxychloroquine insensitive) pathway is predominant in the human lung cells. If you use Vero E6 cells that have been genetically engineered to express the TMPRSS2 enzyme (and thus have the TMPRSS2 pathway too), then hydroxychloroquine loses its ability to inhibit the COVID-19 virus infection of the cells! Other researchers have also found that the inhibition of SARS-CoV-2 entry into cells by hydroxychloroquine is antagonized by the presence of the TMPRSS2 pathway. The above is a bold hypothesis that explains why hydroxychloroquine alone has not been found to work in the best-designed studies (1, 2, 3, 4, 5, 6, 7) performed so far. The reasoning is that it does not work because it doesn’t affect the TMPRSS2 pathway of COVID-19 virus activation that is the predominant viral activation pathway in human airway cells! This hypothesis also eliminates the original rationale to use hydroxychloroquine, which arose from using Vero E6 cells as a screen, and it shows how wise Dr. Fauci was in not giving a lot of importance to that very preliminary 2005 study. Nevertheless, notice I mentioned that the above proposal is just a hypothesis. Some people have interpreted the results to mean that hydroxychloroquine reduces the COVID-19 viral infection in monkeys, not humans. However, hydroxychloroquine does not reduce or prevent COVID-19 infection in macaque monkeys. More studies are needed before we can conclude that this is the reason why hydroxychloroquine doesn’t work in humans. However, if you are one of the people that argue that hydroxychloroquine by itself is not active (has no antiviral activity), but rather that it enhances the uptake of zinc which has the real antiviral action, then this hypothesis does not affect your claim. Whether zinc acts with hydroxychloroquine to ameliorate or prevent COVID-19 remains to be demonstrated in well-designed clinical trials (and several are ongoing). But what we can say right now is that the best evidence we have so far indicates that hydroxychloroquine IS NOT effective by itself or with antibiotics against COVID-19, and it’s time we started accepting this. Micrograph of Vero Cells under green light (100X) by Y tambe is used here under an Attribution-Share Alike 3.0 Unported license. This micrograph was merged with an image of hydroxychloroquine by Fvasconcellos which is the public domain.  Trump and Hydroxychloroquine As I wrote before, it is unfortunate that the president of the United States has endorsed the use of hydroxychloroquine against COVID-19, because this has politicized everything having to do with the perception of this drug by the public. When scientists or non-scientists think about hydroxychloroquine, they should be thinking about it as “a drug” that we are researching to find out whether it’s beneficial against COVID-19. Unfortunately, as I warned before, this is becoming more and more difficult. Now hydroxychloroquine is “the president’s drug”. In the current social mindset if you think hydroxychloroquine works, then some people believe you are for the president and for promoting and using a worthless drug, and if you think hydroxychloroquine doesn’t work, some people believe you are against the president and against saving thousands of lives using a drug that has been proven to work. Any statement about the drug is viewed through these warped lenses. In my exchanges on Twitter, I often encounter individuals who promote many erroneous or ambiguous claims about hydroxychloroquine. I have stated, for example, that we can’t rely on the opinions and experiences of doctors and patients to establish whether the drug works. We need clinical trials. I try to explain that doctors, patients, and all human beings in general including scientists are prone to biases that arise through no fault of their own, and that is why we have procedures such as blind protocols and placebos to guard against these biases. However, my comment is invariably interpreted to mean that I am questioning the qualifications of hundreds of doctors, and the trustworthiness of thousands of patients, because I want to discredit positive results for hydroxychloroquine.
I have also tried to explain that not all clinical trials are well-designed. Just because some trials found that hydroxychloroquine works, that doesn’t mean it works. Just because some trials found that hydroxychloroquine doesn’t work, that doesn’t mean it doesn’t. Scientists have to evaluate the quality of the trials. All clinical trials have limitations, which we have to take into account before we make a decision. The results of one well-designed clinical trial can trump hundreds of poorly designed trials. However, my comments regarding the hydroxychloroquine clinical trials are invariably interpreted to mean that I am trying to discredit the studies that favor the drug because of ulterior motives. As I have stated before, I am a hydroxychloroquine skeptic, but my skepticism towards the drug is not rooted in a desire to shoot it down just because the president promoted it. My skepticism is based on well-designed published studies, soon to be published studies, and reviews that indicate that hydroxychloroquine as a single agent or combined with antibiotics is not effective to treat patients sick with COVID-19 or as a prophylactic to prevent patients from being infected with COVID-19 or at least ameliorating their disease. Below are some of these studies: Reviews Efficacy of Chloroquine or Hydroxychloroquine in COVID-19 Patients: A Systematic Review and Meta-Analysis Update I. A systematic review on the efficacy and safety of chloroquine/hydroxychloroquine for COVID-19 Studies A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19 Effect of Hydroxychloroquine in Hospitalized Patients with COVID-19: Preliminary results from a multi-centre, randomized, controlled trial A Cluster-Randomized Trial of Hydroxychloroquine as Prevention of Covid-19 Transmission and Disease Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19 Hydroxychloroquine for Early Treatment of Adults with Mild Covid-19: A Randomized-Controlled Trial Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19 Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial In addition to the above, the hydroxychloroquine trials at the World Health Organization (Solidarity trial) and the NIH (Orchid trial) were halted when independent reviewers of the data concluded that hydroxychloroquine offered no benefits (these trials have not yet been published).. Early on in the pandemic, the narrative was put forward that patients with Lupus who were taking hydroxychloroquine were less affected, or did not develop COVID-19 with the same severity. But this is not true. Lupus patients on hydroxychloroquine get COVID-19 at rates and severity comparable to Lupus patients not taking hydroxychloroquine. Baseline use of hydroxychloroquine in systemic lupus erythematosus does not preclude SARS-CoV-2 infection and severe COVID-19 Finally, there are also studies with animals that have shown no effects of hydroxychloroquine. Hydroxychloroquine Proves Ineffective in Hamsters and Macaques Infected with SARS-CoV-2 Hydroxychloroquine use against SARS-CoV-2 infection in non-human primates Back in 2005, some observations on the effectiveness of chloroquine were made in an experiment performed in culture on a cell line derived from the kidneys of an African Green Monkey (Vero E6 cells). The results of this experiment have been used nowadays to try to discredit Dr. Fauci. In the article that I quoted above on testing hydroxychloroquine on non-human primates, the authors tested hydroxychloroquine on Vero E6 cells and found that it has an antiviral effect. Then they tried the drug on a model of reconstituted human airway epithelium developed from primary nasal or bronchial cells (a more relevant model) and they found that hydroxychloroquine has no antiviral effect, whereas previously the authors had found that remdesivir did have an antiviral effect in this model. Based on some of the above evidence the FDA revoked its emergency use authorization of hydroxychloroquine. Like I have said many times, all studies have limitations, and it’s healthy to discuss the strengths and weaknesses of studies. But in their comments, many of the apologists of hydroxychloroquine go beyond this, as they infer a nefarious intent behind the limitations of the studies, which they assume to have been introduced into the study protocol on purpose to make hydroxychloroquine (and the president) look bad. If these people have very good evidence that this is the case, then they should present it, otherwise engaging in this innuendo is unwarranted, disrespectful, and unacceptable. Even though I am skeptical of hydroxychloroquine, I don’t want to be right, I want to save lives. If well-designed clinical trials prove that hydroxychloroquine works, then it works, and we HAVE to accept it works; no excuses. However, if well-designed clinical trials prove that hydroxychloroquine doesn’t work, then it doesn’t work, and we HAVE to accept it doesn’t work; no excuses. Whether the president promoted the drug or whether the results of the studies agree with your politics is irrelevant. This is what science is, or at least should be about. Hydroxychloroquine should just be “another drug” being evaluated for COVID-19 by scientists having the best interests of the patients in mind. Hydroxychloroquine should not be “the president’s drug”. Making it the president’s drug fans the biases and prevents a rational appraisal of whether it works or not. Note: after I published this, it was pointed out to me that hydroxychloroquine may work when combined with zinc. I have acknowledged that to establish this we need to wait for the results of several clinical trials that are ongoing. However, the subject of this post is the original claim that was made for hydroxychloroquine: that it works as a single agent or combined with antibiotics. Sure, we will move on to zinc, but first can we agree that the evidence from the best studies indicates that hydroxychloroquine as a single agent or combined with antibiotics DOES NOT work against COVID-19? The photo of President Trump from Whitehouse.gov is in the public domain. This photo was merged with an image of hydroxychloroquine by Fvasconcellos also in the public domain. 7/3/2020 Fighting Coronavirus Misinformation and Conspiracy Theories: Fauci, Hydroxychloroquine, and Retracted ArticlesRead Now Dr. Anthony Fauci Oh dear, so much COVID-19 misinformation, and conspiracy theories, and so little time and space. Let’s get started. Dr. Anthony Fauci is receiving a lot of criticism from people, ranging from those who deny the severity of COVID-19 and think he misadvised the president, promoting the interests of political elites and the deep state, to those who think he is denying the efficacy of hydroxychloroquine and promoting the economic interests of pharmaceutical companies to the detriment of the interests of patients. These people question his character, and call him a liar, a fraud, a traitor, and a saboteur who should be fired. As it turns out, these insults are nothing compared to the insults levied against him when he was coordinating the nation’s response to the AIDS epidemic in the 1980s. The notorious firebrand AIDS activist Larry Kramer criticized Dr. Fauci for moving too slowly in finding a treatment for AIDS, and said he was evil and represented a callous government. Kramer called Fauci a pill-pushing tool of the medical establishment, an incompetent idiot, a disgrace, and a murderer who should be put in front of a firing squad. Kramer compared him to a Nazi and even insulted Fauci’s wife! So what did Dr. Fauci do? He talked to Kramer and other AIDS activists, he heard their concerns, he realized they had a point, and he pushed for changes in the way clinical trials were conducted speeding up the process, making it more flexible, and giving patients a greater voice. He reached out to those who insulted him and worked with them to change medicine for the better and make history. Eventually, Dr. Fauci and Kramer became good friends. Fauci helped Kramer get medical treatment for his health problems, and Kramer made Fauci a character in one of his award winning plays. So when critics say Dr. Fauci doesn’t care for patients or is beholden to special interests, I am skeptical of these claims. I think that history so far indicates that this is not who Dr. Fauci is. This is not to say that Fauci doesn’t make mistakes, but I certainly believe that he is acting in the best interest of the American people. But can’t people change? Sure, but as far as I’m concerned, the burden of proof is on the critics to produce exceptional evidence that there is a nefarious intent behind his actions.  Hydroxychloroquine Another conspiracy theory involving Dr. Fauci states that he has known for 15 years that chloroquine (a drug related to hydroxychloroquine) was effective in hindering the spread of a virus, SARS-CoV, which is 79% related to the COVID-19 virus (SARS-CoV-2), in primate cells in culture based on a study published back in 2005. So it is claimed that Fauci is lying when he says that there is no good evidence for the effectiveness of hydroxychloroquine against COVID-19.
Dr. Fauci is a competent scientist, and he knows that cell culture is a very preliminary step when employed to look for effective drugs. He knows that the results obtained with this method may not hold in more complete models that better reflect the complexity of the full organism. For example, hydroxychloroquine did not have either a therapeutic or prophylactic effect in hamsters and monkeys infected with the COVID-19 virus. This agrees with the best human studies so far that indicate that hydroxychloroquine is not effective. Another conspiracy theory that is making the rounds concerns retracted articles published in the scientific journals, The Lancet, and the New England Journal of Medicine (NEJM). These two journals published studies where scientists examined a database of patients treated with hydroxychloroquine and concluded not only that hydroxychloroquine was not effective, but that it was also harmful to the patients. The results of these studies led to a temporary halt of several hydroxychloroquine trials taking place worldwide. However, when the studies were examined by scientists, numerous discrepancies in the data and problems in its analysis were detected. Letters signed by more than one hundred scientists were delivered to the Lancet and to the NEJM outlining these problems. The journals expressed concerns about these discrepancies, and the authors of the articles retracted them when they were not able to dispel these concerns with the company that provided them with the hydroxychloroquine dataset. The conspiracy argument alleges that the publication of these articles proves that there is a concerted campaign by the scientific establishment to discredit hydroxychloroquine at the expense of the lives of people who could benefit from it, just to embarrass president Trump for advocating the use of this drug. The conspiracy theory argues that this scandal demonstrates that scientists have lost all credibility. However, what this argument ignores is that it was scientists who detected these problems and alerted the journals, and the journals proceeded to raise concerns with the authors, and the authors acknowledged those concerns and retracted the articles when they could not address said concerns. That this happened is not a scandal. Scientists make mistakes all the time. In fact, that is the strength of science. The only reason that science can be right is because it can be wrong. In this case, error was detected, addressed, and removed. The scandal would have been if the problems with the articles had not been addressed and the articles had not been retracted. The fact that the opposite happened is an indication that science worked the way it should, and vindicates our confidence in the scientific process. Finally, another conspiracy theory involves the claim that countries that have embraced the use of hydroxychloroquine are doing better than countries that haven’t. Therefore, the unwarranted rejection of hydroxychloroquine by the health care systems of some countries has led to many preventable deaths. Those that espouse this conspiracy theory do not make any efforts to address other variables that could explain these differences. For example, there is the number of infected people that spread the disease initially in the country (more disease spreaders equals more infections and more problems with the health care system). There is the timing of the spread of the disease (earlier spread means less time to adapt). There is the constellation of drugs and procedures that are used to treat patients (how do you separate the effect of hydroxychloroquine from that of other drugs and/or procedures). There is the age and health of the population affected (younger healthier people are less susceptible). There is the strength and effectiveness of the mitigation measures employed (older sicker people could have been protected better in one country than in another another). There are differences in reporting what constitutes a COVID-19 death from one country to another. If these and other variables are not considered and controlled for, the claim does not go beyond a mere anecdote. The misinformation and conspiracy theories I’ve mentioned are but a fraction of all the bilge that’s out there, but what they all have in common is that they are part of an effort to disqualify mainstream science and scientists as they deal with COVID-19 and evaluate hydroxychloroquine and other drugs. The image of Dr. Fauci ny NIAID is used here under an Attribution 2.0 Generic (CC BY 2.0) license. The image of hydroxychloroquine by Fvasconcellos is in the public domain. I had an exchange on Twitter with people alleging that doctors are finding that the drug hydroxychloroquine is 100% effective against COVID-19 and posting videos of patients claiming they had been cured by this drug. I tried to explain that this evidence is not valid and provided a link to one of my previous posts that addressed these claims. Then I stated that we need to wait for the results of the clinical trials. The response I got was that if doctors and their patients have tried it and are convinced it works, then that’s all the evidence we need. Unfortunately, this is simply not true. Even before hydroxychloroquine came along, the majority of patients hospitalized with COVID-19 would survive. If all patients are treated with hydroxychloroquine, then how do we know which patients got better because of the drug and which got better because they were going to get better anyway, or because of other treatments? In an uncontrolled clinical environment in the middle of a pandemic, patients are not randomized into matched groups and their treatments controlled and blinded to exclude placebo effects and other biases. Patient testimonials and doctor’s opinions are valuable to design clinical trials, but they have many shortcomings and should never be used to establish whether a drug works or not. All doctors know (or should know) this. However, the main point of this post is not to address the claim that hydroxychloroquine is 100% effective against COVID-19, but rather the attitude of scientists towards such claims, especially when they are reported using the media instead of the regular scientific channels. Scientists know that products or therapies that are 100% effective are rare, and this is even more so in the case of major diseases like COVID-19. Some vaccines, hormones like insulin, or a few antibiotics have approached this level of effectiveness, but this is not very common for most other compounds or drugs. About 86% of the drugs tested in clinical trials are found not to be effective and are not approved. Claims of 100% efficacy for a drug or therapy will trigger a strong (and warranted) skeptical response from most scientists.  Quack I have been around a while, and I have read many investigations into multiple bogus claims regarding miracle cures or procedures promoted by quacks. One of the characteristics of these individuals is that they inflate the claims they make regarding the efficacy of their products or therapies beyond the bounds of credibility. If these fraudsters wanted to be believable, they would probably look up the percentage cure rate of the best science-sanctioned therapy and then inflate the claims for their products or therapies by a few percentage points to make them look significantly better but not impossibly so. However, the target audience of these individuals is not scientists but the general public, which has no experience with scientific research or clinical trials and their nuances.
As I have explained before, the best way to promote a bogus product or therapy is to make your audience assimilate your product as part of their identity. If you can achieve this, your audience will be impervious to evidence that the product does not work. This is because any attack on your product will be viewed by the members of your audience as a personal attack on themselves. From this vantage point, it is unfortunate that the president of the United States has promoted the use of hydroxychloroquine. In the current politically charged atmosphere, I am concerned that this identity-forming process seems to be coalescing around the notion that if you don’t accept that hydroxychloroquine works, then you are against the president and thus part of a left-wing conspiracy. It is then all too easy for unscrupulous individuals to exploit this situation by linking themselves to the “pro-president” audience and peddle hydroxychloroquine or other as yet unproven drugs or therapies for COVID-19. If their claims are questioned, all they have to do is argue they are being attacked by the same system that their audience believes is against them and the president. I was skeptical about hydroxychloroquine from the beginning, not because the president promoted it, but because the data for its effectiveness was weak. Thus when I hear these claims for 100% effectiveness of hydroxychloroquine (or any other drug or therapy for that matter), this immediately raises a red flag, and I close my mind to them. This may not seem the scientific thing to do, but remember that keeping your mind too open can be dangerous. As far as I’m concerned, like the late astronomer Carl Sagan said, “Extraordinary claims require extraordinary evidence.”, and the burden of proof is on those individuals who make these claims. It is up to them to produce high-quality evidence to support that what they claim is true, and, seriously, with a 100% success rate this should not prove too difficult, right? At this point you may argue that even if the effectiveness of hydroxychloroquine is less than 100%, but something like 80%, or 50% or 30%, that would still be significant and important. My answer to this is, yes, but this HAS to be established by well-designed clinical trials. At the moment, many clinical trials of hydroxychloroquine are ongoing, and several of these trials are sufficiently well-designed to yield unambiguous results. As I write this, among the best trials completed so far, one has indicated that hydroxychloroquine does not work as a prophylactic against COVID-19, and another has indicated that hydroxychloroquine does not reduce the risk of death among patients hospitalized with COVID-19. The FDA recently revoked its emergency use authorization of hydroxychloroquine, because based on the available evidence it’s unlikely to be effective in treating COVID-19 and any potential benefit from its use outweighs the potential risks. Many of these trials were designed to address the initial claims for hydroxychloroquine being very effective when administered alone or with certain antibiotics. A new claim has been made that hydroxychloroquine is only effective when it is administered with zinc, and new clinical trials are being performed to evaluate this possibility. As I stated above, I am skeptical about hydroxychloroquine, but I don’t want to be right, I want to save lives, and I hope the combination of hydroxychloroquine with zinc works. However, the public has to understand and accept the need to perform clinical trials and stop relying on testimonials and other anecdotal evidence. Image of a quack doctor selling remedies from his caravan; satirizing Gladstone's advocacy of the Home Rule Bill in Parliament is a Chromolithograph by T. Merry, 1889, and comes from the Welcome Collection. The image was modified and used here under an Attribution 4.0 International (CC BY 4.0) license, and no endorsement by the licensor is implied. |
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